Chronic pancreatitis remains a common and challenging clinical syndrome. Its cardinal feature, pain, has been difficult to treat effectively despite a multitude of empirical therapeutic approaches. Our laboratory has been actively pursuing the molecular pathogenesis of pain in pancreatitis for over a decade. In the process we have established highly useful and relevant rodent models of CP and gained valuable insight into the contribution of specific molecules, particularly voltage dependent (Kv) and TRPV1 ion channels and nerve growth factor, NGF. However, it is clear that there is much more that we need to learn. In this proposal, we will focus on a previously under scribed role of transforming growth factor beta, (TGF?) in the pathogenesis of chronic inflammatory pain. Although TGF? is prominent in the inflammatory mileu, its participation in nociceptive sensitization has received little attention. Our hypothesis is that TGF? is an important modulator of sensory neuronal function and plays a major role in the pathogenesis of pain in chronic pancreatitis via changes in pancreas-specific sensory neuronal excitability and ion channel function. In this proposal, we will attempt to prove this hypothesis, using a comprehensive multidisciplinary approach encompassing molecular, electrophysiological and behavioral assays, via the following specific aims: (1) To determine the effects of TGF? on sensory neuronal excitability and ion channel activity in vitro (2) To determine the effects of exogenous TGF? on pain behavior and pancreatic sensory neuronal plasticity (in vivo) (3)To determine the role of endogenous TGF? in the pathogenesis of pain behavior and sensory neuronal plasticity in chronic pancreatitis. The significance of this proposal is two-fold. First, it will provide a better understanding of the pathogenesis of pain in chronic pancreatitis. Secondly, it will establish a major new biological role for TGF?, opening up the possibility of its involvement in many other chronic painful disorders that may be inflammatory or neoplastic in origin. PUBLIC HEALTH RELEVANCE: This aim of this proposal is to understand the way in which inflammation in the pancreas causes pain and increases the activity of nerves that carry pain signals. Specifically, we are focusing on the role in this process of a molecule called transforming growth factor- beta, which has previously been implicated in the development of fibrosis.